Temporal trends in treatment outcomes of acute lymphoblastic leukemia in Japan: Progress and unmet needs

Abstract Background The prognosis of acute lymphoblastic leukemia (ALL) has improved globally with advances in diagnostic techniques and therapeutic agents. However, real-world data from Japan, particularly from the period since the introduction of these agents in 2018, remain limited. Methods To evaluate the outcomes of ALL, we retrospectively analyzed patients who received treatment at Toranomon Hospital between January 2011 and October 2024. The analysis was limited to patients diagnosed with ALL either at the time of initial diagnosis at our hospital or upon transfer. Treatments included chemotherapy, radiotherapy, or allogeneic hematopoietic stem cell transplantation (allo-HSCT), excluding cases treated solely with total body irradiation. Patients who initiated treatment at other institutions were included if they subsequently received treatment at our hospital. The primary endpoint was the 5-year overall survival (OS) rate, defined as the period from initial diagnosis to death or the cut-off date (March 31, 2025). Patients were categorized into 2 groups by diagnosis year: pre-2018 and post-2018, corresponding to the period before and after the introduction of blinatumomab and inotuzumab ozogamicin at our institution. OS was estimated using the Kaplan-Meier method, and group comparisons were performed using the log-rank test. For multivariate analysis, Cox proportional hazards models with forced entry were used. All tests were 2-sided, and p-values < 0.05 were considered statistically significant. Result A total of 278 patients with ALL were included in this analysis. The median age was 47 years (range, 15–87), and 183 patients (65.8%) were male. Patients were stratified into 3 age groups: 97 (34.9%) were classified as adolescents and young adults (AYA; 15–39 years), 114 (41.0%) as middle-aged (40–59 years), and 67 (24.1%) as elderly (≥ 60 years). Regarding ALL subtypes, 52 patients (18.7%) had T-cell ALL (T-ALL), 118 (42.4%) had Ph-positive B-cell ALL (Ph+ B-ALL), and 107 (38.5%) had Ph-negative B-cell ALL (Ph– B-ALL). Regarding treatment, 61 patients (21.9%) received chemotherapy alone, while 217 (78.1%) underwent allo-HSCT. Notably, 58 patients (20.8%) underwent ≥ 2 allo-HSCTs. As for baseline cytogenetics, a normal karyotype was observed in 59 patients (21.2%), complex karyotype in 39 (14.0%), TCF3::PBX1 fusion in 10 (3.6%), KMT2A-rearranged in 10 (3.6%), and other abnormalities in 49 (17.6%). The 5-year OS rate for the entire cohort was 54.3% (95% CI, 48.2–61.1). When stratified by year of diagnosis, the post-2018 group demonstrated significantly better 5-year OS compared to the pre-2018 group (71.7% vs. 44.0%, p < 0.001). In contrast, no significant difference in 5-year OS was observed among the 3 age groups (55.6% vs. 51.6% vs. 56.8%, p = 0.82). By ALL subtype, B-ALL showed better OS compared to T-ALL (Ph+ B-ALL: 64.2%, Ph– B-ALL: 54.2%, T-ALL: 37.4%; p < 0.001). Subgroup analysis by age revealed significantly better OS in the post-2018 group among middle-aged (72.3% vs. 36.7%, p < 0.001) and elderly patients (80.3% vs. 44.4%, p = 0.015), whereas no significant improvement was observed among AYA patients (65.3% vs. 50.9%, p = 0.13). Regarding ALL subtypes, the post-2018 cohort showed markedly improved OS in Ph+ B-ALL (83.2% vs. 46.4%, p < 0.001) and Ph– B-ALL (68.6% vs. 48.4%, p = 0.047), but not in T-ALL (47.8% vs. 31.0%, p = 0.28). Multivariate analysis adjusting for key clinical and cytogenetic variables identified initial diagnosis in or after 2018 (hazard ratio [HR], 0.35; p < 0.001) and B-ALL subtype (HR, 0.54; p = 0.018) as significant favorable prognostic factors for OS. Conclusion In the comparison by diagnostic period, patients diagnosed in or after 2018 showed improved 5-year OS compared to those diagnosed before 2018. This improvement may reflect the implementation of appropriate strategies guided by measurable residual disease (MRD) monitoring and the availability of novel agents, such as tyrosine kinase inhibitors and antibody-based therapies. However, outcomes for T-ALL and AYA patients did not improve over time, likely due to the absence of newly effective agents for T-ALL and a higher proportion of refractory cases, such as Ph-like ALL, in the AYA group. Further efforts are needed to establish effective treatment strategies for subgroups that have not benefited from recent therapeutic advances.